LAUSR

T cell-based immunotherapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses due to presence of immune-refractory tumor cells that limits its clinical success by blocking amplification of anti-tumor immunity cycle. Previously, we found that immune selection by T-cell based immunotherapy drives the evolution of tumors toward immunotherapeutic refractoriness including multimodal resistant and stem-like phenotype via activation of NANOG-TCL1A-AKT axis. Here, we report a crucial role of HSP90A at the crossroads between NANOG-TCL1A axis and the refractoriness of immune-edited tumor cells by identifying HSP90AA1 as a novel NANOG transcriptional target. Furthermore, we found that TCL1A is a novel client of HSP90A, and demonstrated that HSP90A potentiates AKT activation through TCL1A stabilization and thereby contributes to refractoriness in NANOGhigh immune-edited tumor cells. Importantly, inhibition of HSP90A sensitizes immune-refractory tumor cells to T cell-based immunotherapy and elicits effective anti-tumor response by re-invigorating anti-tumor immune cycle of tumor-reactive T cells. Our findings implicate that the NANOG-HSP90A pathway is a central molecular axis and a potential target for immune-refractory tumor. Citation Format: Se Jin Oh, Tae Woo Kim, Kwon-Ho Song, Suyeon Kim. NANOG-HSP90A axis confers immunotherapeutic resistance by blocking anti-tumor immunity cycle [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1033.